Intravenous Iron-Induced Hypophosphatemia: an Emerging Syndrome

UCLA UCLA Previously Published Works

Title Intravenous Iron-Induced Hypophosphatemia: An Emerging Syndrome.

Permalink https://escholarship.org/uc/item/9p6232r3

Journal Advances in therapy, 38(7)

ISSN 0741-238X

Authors Glaspy, John A Wolf, Myles Strauss, William E

Publication Date 2021-07-01

DOI 10.1007/s12325-021-01770-2

Peer reviewed

eScholarship.org Powered by the California Digital Library University of California Adv Ther (2021) 38:3531–3549 https://doi.org/10.1007/s12325-021-01770-2

REVIEW

Intravenous Iron-Induced Hypophosphatemia: An Emerging Syndrome

John A. Glaspy . Myles Wolf . William E. Strauss

Received: March 15, 2021 / Accepted: April 30, 2021 / Published online: May 30, 2021 Ó The Author(s) 2021

ABSTRACT have documented the persistence of HPP for several weeks or even months, the lack of Some, but not all, intravenous iron formula- studies lasting beyond 5–6 weeks has con- tions have been recognized to induce renal strained full understanding of the duration of phosphate wasting syndrome. Most commonly effect. Clinical trials have established that the this has been reported following treatment of mechanism involves the bone/metabolic axis iron deficiency anemia (IDA) with ferric car- with the elevation of intact fibroblast growth boxymaltose (FCM). A search of PubMed iden- factor 23 playing the central role. Reports con- tified relevant randomized controlled trials tinue to accumulate of the clinical conse- (RCTs), and case studies evaluating hypophos- quences of severe HPP which are, most phatemia (HPP) resulting from intravenous iron commonly, bone abnormalities following treatment. While more recent larger compara- repetitive dosing. Case reports and studies, tive RCTs have confirmed that the majority of however, have also shown that symptomatic patients receiving FCM, especially those with hypophosphatemia can occur after a single FCM normal renal function, may experience severe dose. The frequency of such events remains HPP, complete documentation is hampered by unknown, in part due to lack of awareness of inconsistent reporting of serum phosphate in hypophosphatemia coupled with the fact that such trials. Similarly, while case series and RCTs the most common acute symptoms of HPP (fatigue and weakness) are the same for IDA and for many of the chronic diseases that cause IDA. & J. A. Glaspy ( ) Changes to US and European prescribing infor- Division of Hematology-Oncology, Department of Medicine, UCLA School of Medicine, Los Angeles, mation for FCM should raise awareness of the CA 90095, USA potential for HPP and need to monitor patients e-mail: [email protected] at risk for it.

M. Wolf Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, NC, Keywords: Ferric carboxymaltose; Ferric USA derisomaltose; Ferumoxytol; Iron deﬁciency M. Wolf anemia; Iron-induced hypophosphatemia; Iron Duke Clinical Research Institute, Duke University treatment; Osteomalacia School of Medicine, Durham, NC, USA

W. E. Strauss AMAG Pharmaceuticals Inc., Waltham, MA, USA 3532 Adv Ther (2021) 38:3531–3549

a patient with IV iron-induced hypophos- Key Summary Points phatemia was reported in 2009 in New Zealand [5]. This relationship which was later conﬁrmed Some, but not all IV irons induce a renal in a prospective study [6]. Since these early phosphate wasting syndrome, most publications, there have been numerous reports frequently with ferric carboxymaltose. of hypophosphatemia associated with IV iron administration [7]. Multiple IV iron formula- Once considered both transient and tions have been implicated, including saccha- clinically benign, accumulating evidence rated iron oxide [7] and ferric carboxymaltose indicates that this is not the case. (FCM) [7–10], which is responsible for most of Case series and randomized controlled the cases in the European Union and North trials have documented that the resultant America. Initially, IV iron-induced hypophos- severe hypophosphatemia may persist for phatemia was thought to be asymptomatic, self- several weeks and even months. limited, and not associated with adverse events or clinical sequelae [10–14]; however, evidence Accumulating case reports note the is accumulating that this is not always the clinical sequelae, most notably fractures case [7, 15–21]. and other bone abnormalities following In their 2017 review, Zoller and colleagues repeat doses; however, acute symptomatic elegantly outlined the then current under- events have occurred following a single standing of the mechanism of iron-induced administration. hypophosphatemia and summarized the clini- Recognition of these events is hampered cal cases reported in the literature up to that by the fact that the most common point [7]. The purpose of this review is to symptoms are similarly associated with describe recent studies on the incidence, dura- the underlying disease states; recent tion, risk factors, mechanism of IV iron-induced changes in US and European prescribing hypophosphatemia and to catalog the expand- information will hopefully enhance ing list of clinical cases since the 2017 awareness of this syndrome. review [7].

METHODS

A search of PubMed identified clinical studies DIGITAL FEATURES published from 2008 to 2020 based on com- prehensive search terms for iron-deficiency This article is published with digital features, anemia (IDA) and US marketed IV iron formu- including a summary slide, to facilitate under- lations. There were 20 randomized controlled standing of the article. To view digital features trials (RCTs) that reported on serum phosphate for this article go to https://doi.org/10.6084/ or hypophosphatemia. Of these, 19 out of 20 m9.figshare.14501688. evaluated FCM, five evaluated iron sucrose, and one each evaluated iron dextran and ferumoxytol. In addition nine observational, retro- INTRODUCTION spective or post hoc studies were identified; all evaluated FCM, with two also reporting on iron Hypophosphatemia was first described as a sucrose. Fourteen case studies reporting complication of intravenous (IV) iron treatment hypophosphatemia related to IV iron treatment in Japanese patients receiving long-term daily were also identified and included in the evalu- treatment with IV saccharated ferric oxide [1–4]. ation. An additional nine relevant papers are The first case of significant and prolonged ele- referenced in this review relating to hypophos- vation of fibroblast growth factor 23 (FGF23) in phatemia, FGF23, IDA, and iron treatment. This Adv Ther (2021) 38:3531–3549 3533 article is based on previously conducted studies patients receiving FCM versus ferumoxytol and does not contain any new studies with (severe: 50.8% versus 0.9%; extreme: 10.0% human participants or animals performed by versus 0.0%; P \ 0.001 for each) [10]. Recently any of the authors. reported results of pooled data from two identical randomized studies (the PHOSPHARE trials) that compared FCM (two doses of 750 mg RESULTS administered 1 week apart) to ferric derisomaltose (one dose of 1000 mg) in patients with IDA Incidence also noted a significantly higher rate of hypophosphatemia among patients treated The majority of cases of hypophosphatemia, with FCM versus those treated with ferric deri- either symptomatic or based on serum phos- somaltose (74.4% versus 8.0%; P \ 0.001). Sev- phate testing, have occurred following FCM ere hypophosphatemia (B 1.0 mg/dL) was not administration, with rates reported in the liter- observed in any patient treated with ferric ature generally from approximately 40% to derisomaltose, but developed in 11.3% of FCM- 70%. However, a recent systematic review of the treated patients [23]. literature for the past 10 years showed that only An unanswered question is why the inci- 32% (20 of 63) of RCTs investigating IV iron dence of hypophosphatemia is markedly higher formulations marketed in the USA for IDA with certain IV iron formulations versus others. reported on serum phosphate and/or However, so far, no studies have elucidated the hypophosphatemia [9]. Further, it was noted mechanism. that the methods for measurement and reporting of serum phosphate and hypophosphatemia Duration of Effect were highly variable, even among current prospective trials. The absence of standard pro- Although initial investigations suggested that tocols for assessing and monitoring phosphate hypophosphatemia following treatment with levels, and variability in the reporting, defini- FCM typically lasted for 2–3 weeks, recent tions, and follow-up of hypophosphatemia studies have demonstrated that it can be sub- make it difficult to assess the true incidence of stantially longer. In the FIRM trial, 29.1% of this syndrome. It is likely that inconsistent patients treated with FCM remained assessment of hypophosphatemia has con- hypophosphatemic at the end of the 5-week tributed to an underestimation of its actual study period, including 4.7% with extreme prevalence, clinical significance, and the gen- hypophosphatemia, compared with none of the eral lack of awareness of hypophosphatemia ferumoxytol-treated patients [10]. Likewise, among clinicians. hypophosphatemia persisted at day 35 in 43.0% Recent clinical trials paint a clearer picture. of FCM-treated patients in the trials that com- The FIRM trial was one of the largest (N = 1997) pared FCM to ferric derisomaltose [23]. Similar head-to-head phase 3 randomized, double- results have been observed outside of RCTs. In a blind, controlled trials of IV iron formulations. chart review of 130 patients treated with either It compared rates of hypersensitivity reactions, iron sucrose (mean dose 701 mg) or FCM (mean including anaphylaxis, in response to a single dose 2123 mg) between January 2012 and course of FCM (two doses of 750 mg adminis- December 2014 the mean duration of tered 1 week apart) or ferumoxytol (two doses of hypophosphatemia in the iron sucrose group 510 mg administered 1 week apart) [22]. A pre- was between 2 and 18 weeks, while the mean specified secondary outcome was the incidence duration in the FCM group was 6 months, with of, and clinical risk factors for, hypophos- some patients never reaching normal phos- phatemia. The incidence of severe hypophos- phate levels during the 2-year study period [24]. phatemia (serum phosphate \ 2.0 mg/dL) and The persistence of IV iron-induced extreme hypophosphatemia (serum phos- hypophosphatemia is illustrated by two phate \ 1.3 mg/dL) was significantly higher in 3534 Adv Ther (2021) 38:3531–3549 patients from a 2014 case series [25]. Both markers of bone metabolism such as bone developed hypophosphatemia (one had a serum alkaline phosphatase. phosphate levels 0.25 the other 0.28 mmol/L) Another limitation in the available dataset is after infusions of FCM. Both were treated orally the absence of trials that prospectively and or intravenously with phosphate and their systematically collected and reported data phosphate levels improved or normalized. specifically pertaining to adverse clinical However, their phosphate levels declined again sequelae of hypophosphatemia. These were not such that one patient had a phosphate level of reported in the FIRM or PHOSPHARE trials, 0.17 mmol/L 3 days later requiring further leaving open the question regarding whether phosphate treatment. The other patient had and to what extent they occur, when significant persistent hypophosphatemia (0.2 mmol/L) hypophosphatemia follows iron infusion. The despite being on oral phosphate therapy and adverse sequelae of hypophosphatemia were required two IV courses of phosphate to nor- not specifically sought in these trials, although malize her levels over the next 7 weeks. Her any and all adverse events were collected and phosphate levels remained low over the subse- adjudicated. While the incidence of hypophos- quent month, despite continued oral phosphate phatemia secondary to FCM was elevated, the and cholecalciferol treatment [25]. The mecha- rate of symptomatic events is likely less and nism for the recurrent/persistent hypophos- may be undetected in cohorts of this size. phatemia demonstrated by these cases despite treatment and ‘‘temporary’’ improvement of Pathophysiologic Mechanisms of IV Iron- serum levels remains unknown; however, it Induced Hypophosphatemia likely involves persistent increase in FGF23 and parathyroid hormone (PTH). Clinically, the Working through multiple feedback loops, PTH, cases suggest the need for the monitoring of 1,25-dihydroxyvitamin D [1,25(OH)2D], and serum phosphate levels after IV iron supple- FGF23 regulate serum phosphate by modulating ments, at least in situations of severe intestinal phosphate absorption, renal phos- hypophosphatemia for at least a month or two phate reabsorption, and bone metabolism [28]. after termination of IV iron treatment. Malfunction of these feedback loops may result Hindering a more complete understanding in several diseases. Primary increases in FGF23 of the usual duration of hypophosphatemia has cause hypophosphatemia and suppression of been the fact that almost all the controlled 1,25(OH)2D, which leads to rickets or osteo- prospective trials are relatively short (ca. malacia. Secondary increases in FGF23 are one 35 days) [22, 23, 26, 27]. In these studies, a high of the earliest indicators of declining renal percentage of the FCM patients had severe function, and the magnitude of FGF23 eleva- hypophosphatemia at the end of the 5-week tion is strongly associated with and may con- follow-up. It is unknown how much longer it tribute to increased future risk of cardiovascular would have persisted if surveillance continued. disease and death [29–41]. In an observational 6-week study of patients The role of 1,25(OH)2D in IV iron-induced with inflammatory bowel disease after a single hypophosphatemic-related osteomalacia was 1000 mg FCM dose, 56.9% of patients had reported as early as 1997 [3]. It was not until moderate-to-severe hypophosphatemia at 2009, however, that the role of FGF23 in week 2 and 13.7% of patients still had it at mediating phosphate wasting was first proposed week 6 [26]. The case reports and chart reviews [6]. The bone/metabolic axis and the interplay highlight the major unmet medical need for with iron deficiency and treatment of IDA with well-controlled, longer-term data on the dura- IV iron formulations was further elucidated in a tion of hypophosphatemia following treatment. randomized study of 55 women with IDA In concert, more data are needed on patients caused by abnormal uterine bleeding who were who receive repeated courses of FCM treatment. treated with either FCM or iron dextran. The This includes pre and post levels of FGF23 and study hypothesized that some IV iron Adv Ther (2021) 38:3531–3549 3535 formulations induce renal phosphate wasting Risk Factors by inhibiting the degradation or cleavage of FGF23, thus leading to an increase in intact Two recent studies have attempted to identify FGF23 [26]. The study evaluated the association which patients may be at greatest risk for of IDA with plasma measurements of both hypophosphatemia [10, 42]. The first was a intact FGF23 (iFGF23) and C-terminal FGF23 prospective, observational study designed to (cFGF23). The iFGF23 assay detects full-length describe the change in FGF23, serum phos- biologically active FGF23 exclusively; the phate, and markers of bone and iron metabo- cFGF23 assay detects both the full-length pep- lism and to identify clinical and biochemical tide, but also its C-terminal cleavage fragments. predictors of low serum phosphate after a single Iron deficiency stimulates increased transcrip- IV infusion of FCM (1 g). The study population tion of FGF23, but this is balanced by an (N = 65) included three groups of women with increase in cleavage of the FGF23. The net result iron deficiency: pregnant women in their sec- is marked elevations of cFGF23 (due to elevated ond or third trimester with no renal abnormal- levels of C-terminal fragments), but normal ities, women with stage 3a–4 non-dialysis- iFGF23 levels and thereby normal serum phos- dependent chronic kidney disease (CKD), and a phate levels. At baseline, the iron-deficient group of controls comprised of women with subjects had markedly increased levels of menorrhagia or gastrointestinal sources of iron cFGF23. Both treatments led to an 80% decline loss with normal renal function. Following in cFGF23 within 24 h. Treatment with FCM, treatment with FCM, iFGF23 increased 2.8–5.4- but not iron dextran, was associated with a fold. FEPi increased in all cohorts with the significant increase in intact FGF23 levels greatest increase in those with CKD, with within 24 h, a subsequent increase in urinary decreases in phosphate levels of 56–76%. Key fractional excretion of phosphate (FEPi), and predictors of serum phosphate decline were low decreases in serum phosphate, 1,25(OH2)D, and baseline phosphate level and weight-adjusted calcium levels, and also increases in PTH [27]. iron dose (FCM/kg). Of interest, although at These results confirmed and further elucidated nadir the phosphate level remained higher than the previous reports of acute FGF23-mediated with the other two groups, the percentage phosphate wasting after treatment with IV iron decrease in phosphate and increase in FEPi fol- formulations [1–4, 6]. lowing FCM was greatest in those with CKD. Recent randomized clinical trials have con- Thus, despite the kidney having impaired abil- firmed that increased FGF23 activates the cas- ity to excrete phosphate, FCM was able to dra- cade leading to hypophosphatemia after matically increase clearance further [42]. treatment with FCM. Results of a pre-planned The second study was a preplanned multi- secondary analysis from the FIRM trial showed variable analysis of data from the FIRM trial, that FCM, but not ferumoxytol, rapidly which showed that treatment with FCM versus increased iFGF23 levels [10]. Similarly, the ferumoxytol was the strongest independent risk pooled analysis of the two separate but identical factor for incident hypophosphatemia (odds PHOSPHARE trials also showed increased intact ratio [OR] 250.6, 95% CI 115.4–544.5) [10], FGF23 levels with FCM, increased urinary FEPi, followed by the presence or absence of CKD. decreased serum 1,25(OH)2D, decreased ionized Baseline serum phosphate, abnormal uterine calcium, and increased PTH (Fig. 1). This study bleeding as the etiology of IDA, and lower body extended our understanding of the interplay of weight were also independent risk factors. these hormones and factors with bone meta- Other risk factors included higher estimated bolism by demonstrating significant elevations glomerular filtration rate (eGFR) and hemoglo- in biomarkers of bone turnover (Fig. 1i) that are bin. CKD as the etiology of IDA was associated associated with osteomalacia [23]. with lower risk. The effects of lower body weight and serum phosphate strengthened as risk factors for persistent hypophosphatemia, while 3536 Adv Ther (2021) 38:3531–3549 Adv Ther (2021) 38:3531–3549 3537 b Fig. 1 LS mean changes from baseline in biomarkers of Finally, and perhaps most hypothesis generat- mineral and bone homeostasis according to iron treatment. ing, is that women with abnormal uterine Red arrows indicate infusion of ferric carboxymaltose, bleeding as the cause of their IDA are more 750 mg; blue arrows indicate infusion of iron isomaltoside, likely to develop hypophosphatemia [10]. 1000 mg. *P \ 0.05, **P \ 0.01, ***P \ 0.001 between- Whether that is due to their being younger with group comparisons from a mixed model for repeated perhaps better preserved renal function, or due measures analysis with treatment day, treatment-by-day, to their iron deficiency being inadequately trial and stratum as fixed effects and baseline value and addressed for an extended period, or some other baseline value-by-day as covariates; safety analysis set. factor, is unknown. FCM, ferric carboxymaltose; FGF23, fibroblast growth Patients with chronic recurrent blood loss factor 23; IIM, iron isomaltoside 1000/ferric derisomal- such as occurs with abnormal uterine bleeding tose; LS, least squares; SE, standard error. Reproduced with or inflammatory bowel disease may have permission from JAMA. 2020;323(5):432–443. Copy- chronic and severe iron deficiency that can rightÓ(2020) American Medical Association. All rights reserved. stimulate FGF23 transcription. Not only may this place such patients at greater risk of acute hypophosphatemia but, when coupled with repeat dosing of FCM which causes prolonged black race emerged as an additional indepen- inhibition of FGF23 cleavage, it may make them dent risk factor [10]. a greater risk for osteomalacia and other bone These reports suggest a number of factors abnormalities [7, 27]. that appear to increase risk. The most important is which IV iron formulation is administered, New Cases of Symptomatic with by far the highest incidence of hypophos- Hypophosphatemia phatemia occurring with FCM administration. Second most important is whether or not the patient has renal dysfunction [7, 10, 42]. Since the 2017 review [7] a number of new case Mechanistically this should not be a surprise reports of iron-induced hypophosphatemia since the inability to clear phosphate is well have emerged. Table 1 presents the salient fea- recognized as an issue in patients with advanc- tures of the reports. These can perhaps be cate- ing kidney disease, although in the FIRM study gorized as those presenting as bone even those with CKD (21.5%) developed severe abnormalities secondary to repeat courses of hypophosphatemia. This was far less than the treatment, as were the earliest reports of symp- 64% rate in those without CKD [10], but still tomatic hypophosphatemia following IV iron significant, demonstrating that the reduced treatment, and more acute presentations after a ability to clear phosphate in CKD is not absolute single course. protection. Some risk factors are perhaps less Several reports note severely symptomatic intuitive. As noted, the impact of body weight musculoskeletal sequelae after repeated dosing was demonstrated in both the single-arm study with IV iron formulations, most commonly of three different cohorts [42] and the large FCM. As noted, almost all occurred following comparative study of ferumoxytol vs FCM [10]. repetitive dosing for a year or longer, resulting Since the patients in both studies received a in not only osteomalacia but generally radio- fixed dose of FCM, the mg/kg dose was higher logic evidence of fractures (Fig. 2). with lower body weight. Although ‘‘lower dose’’ Although the majority of bone involvement may attenuate risk, it should be noted that due to repetitive IV dosing with iron has hypophosphatemia had occurred following the occurred in patients with Crohn’s disease, it has first 750 mg of FCM in a double-blind RCT [22] been reported with other gastrointestinal dis- and has resulted in symptomatic events even orders with chronic or recurrent bleeding, such after a 500 mg dose [15]. Not surprisingly, the as gastric antral vascular ectasia or hereditary lower the baseline phosphate, the greater the hemorrhagic telangiectasia. likelihood of hypophosphatemia [10, 42]. Table 1 Recent hypophosphatemia cases reported in the scientific literature 3538 Patient Relevant history Prior treatment Presentation Laboratory findings Diagnosis 45-year- Crohn’s disease FCM total of 27 g Proximal muscle weakness Hypophosphatemia (serum Hypophosphatemia and old man IDA over 3 years Bilateral groin and shoulder pain phosphate 0.46 mmol/L) osteomalacia with bilateral [46] Increased FEPi (46%) symmetric pseudofractures in the femur necks with IDA Elevated FGF23 (173 pg/ mL) Normal PTH and 25-OH- vitamin D Mild hypocalcemia 38-year- Crohn’s disease FCM 1 g/month for Bilateral hip pain with inability to Hypophosphatemia (serum FGF23-mediated osteomalacia old man IDA 8 months walk phosphate 0.34 mmol/L) [20] Costal and sternal pain Elevated FGF23 (226 ng/L) Multiple hip fractures of the Low calcium (1.97 mmol/L) femoral heads Low 25-OH-vitamin D (18 ng/mL)

Low 1,25(OH)2D (8 pg/ mL) Normal PTH and calcinuria Phosphaturia 19.4 mmol/ mmol of creatininuria

Phosphate reabsorption rate 38:3531–3549 (2021) Ther Adv 60% d hr(01 38:3531–3549 (2021) Ther Adv Table 1 continued Patient Relevant history Prior treatment Presentation Laboratory ﬁndings Diagnosis

45-year- Crohn’s disease FCM Q8 weeks for 4-month history of progressive Low 1,25(OH)2D Hypophosphatemic old man IDA 4 years bone pain in ribs, spine, and feet (19 pmol/L) osteomalacia [47] Acute bone fractures of the ribs, Elevated intact serum femoral head, and metatarsals FGF23 ([ 5 9 ULN) History of hypophosphatemia (serum phosphate 0.21–0.80 mmol/L) 65-year- IDA secondary to gastric Iron polymaltose 2-year history of minimal trauma Hypophosphatemia (serum Hypophosphatemic old antral vascular ectasia 1 g/month for fractures of the wrist, ribs, phosphate 0.29 mmol/L) osteomalacia with multiple woman 13 months sacrum, right pubis TmP/GFR (0.76) and insufﬁciency fractures [17] Compression fracture of the T6 fractional phosphate vertebra excretion (16%) consistent Worsening generalized bone pain with renal phosphate wasting Normal urine calcium, pH, amino acid, glucose, and protein levels 3539 3540 Table 1 continued Patient Relevant history Prior treatment Presentation Laboratory ﬁndings Diagnosis

58-year- IDA secondary to Iron polymaltose 6-month history of bone pain Hypophosphatemia (serum Severe hypophosphatemia and old hereditary hemorrhagic 1 g/month for involving the chest wall, back, phosphate 0.43 mmol/L) sacral and lumbar insufficiency woman telangiectasia 17 months lower limb’s and arms fractures Low 1,25(OH)2D [17] Insufficiency fractures of the ribs (32 pmol/L) Diffusely increased osteoblastic Elevated PTH (8.3 pmol/L) activity compatible with Elevated FGF23 (285 pg/ metabolic bone disease mL) TmP/GFR (0.48) and fractional phosphate excretion (24%) consistent with renal phosphate wasting 73-year- IDA secondary to gastric Total of 11 g FCM 10-month history of upper and Hypophosphatemia (serum Hypophosphatemia insufficiency old antral vascular ectasia (as 1 g infusions) lower limb muscle pain, phosphate 0.27 mmol/L) fractures woman over a 2-year weakness, back pain, and Hypocalcemia (corrected [18] period deteriorating mobility without calcium 2.04 mmol/L) falls Low 25-hydroxyvitamin D Bilateral insufficiency fractures of (32 nmol/L) the sacral wings Increased PTH 29.8 pmol/ Degenerative changes L and ALP (229 IU/L) d hr(01 38:3531–3549 (2021) Ther Adv Acute left L5 transverse process Increased 24-h urinary fracture and fracture of the phosphate excretion lateral mass of sacrum 92 mmol/day d hr(01 38:3531–3549 (2021) Ther Adv Table 1 continued Patient Relevant history Prior treatment Presentation Laboratory findings Diagnosis

42-year- Crohn’s disease FCM 1 g/month for Diffuse skeletal pain (lumbar and Hypophosphatemia (serum FGF23-related old man Ileocecal resection and ca. 1.5 years thoracic spine, ribs, lower phosphate 0.50 mmol/L) hypophosphatemic [16] multiple surgical extremities), gait disturbance, 24-h urine phosphate osteomalacia resections of the small and progressive loss of mobility excretion indicative of intestine Osteomalacia renal phosphate wasting IDA (524 mg) Serum calcium, PTH, and 25-hydroxyvitamin D within the reference range 57-year- Crohn’s disease poorly 26 monthly 1.5-year history of joint and bone Normo-calcemia with FCM-induced old man responsive to multiple infusions of FCM pain elevated alkaline hypophosphatemia with [19] therapies 750 mg over Osteoporosis phosphate and PTH, and autosomal dominant 2 bowel resections about 2 years low-normal phosphate hypophosphatemic rickets level precipitated by iron deﬁciency IDA TmP/GFR suggestive of renal phosphate wasting Pseudofractures Osteomalacia 38-year- IDA—caused by heavy FCM 500 mg (2 Tiredness Hypophosphatemia (serum FGF23-related old menstrual bleeding infusions) 4 and Diffused muscle pain phosphate 0.23 mmol/L) hypophosphatemia and renal woman 3 weeks prior to phosphate wasting Vitamin D deﬁciency Weakness Slightly low albumin- [15] presentation adjusted calcium (1.99 mmol/L)

Low 1,25(OH)2D (12 lg/ L) TmP/GFR (0.21 mmol/L)

suggestive of renal wasting 3541 3542 Table 1 continued Patient Relevant history Prior treatment Presentation Laboratory ﬁndings Diagnosis

33-year- IDA FCM 750 mg (2 Fatigue and shortness of breath Hypophosphatemia (serum Hypophosphatemia old courses) increasing over 3 weeks phosphate 1.2 mg/dL) woman Mild tenderness in the thighs PTH 38.7 pg/mL [21] 25(OH)vitamin D (22.0 ng/mL) C-terminal FGF-23 (116 RU/mL) Hyperphosphaturia (FEPi 99.76%) 45-year- Post gastric bypass Oral iron Asthenia, weakness, and Hypophosphatemia (serum Hypophosphatemia old surgery supplementation generalized muscle pain phosphate 0.9 mg/dL) woman (for about PTH 179 pg/mL [48] 5? years at max Normal calcium, vitamin D, doses) magnesium, plasma Iron sucrose creatinine, and 24-h urine (20 mg/mL phosphorus monthly for ca. 10 months) Iron carboxymaltose (50 mg/mL

monthly for 38:3531–3549 (2021) Ther Adv 5 months) d hr(01 38:3531–3549 (2021) Ther Adv Table 1 continued Patient Relevant history Prior treatment Presentation Laboratory ﬁndings Diagnosis

34-year- IDA FCM (2 infusions Significant decrease (of Hypophosphatemia (serum Renal phosphate wasting old Laparoscopic subtotal 1 week apart; last 0.29 mmol/L) in post-surgical phosphate levels secondary to FGF23 excess woman colectomy infusion 6 days phosphate levels led to 0.37–0.58 mmol/L) [49] before surgery) prolongation of hospitalization Low levels of 1,25 (OH)2D Significantly increased FEPi (29.8%) suggestive of renal phosphate wasting 62-year- Type 2 diabetes Oral iron Continued intense asthenia Hypophosphatemia (serum Severe hypophosphatemia old Arterial HTN supplementation phosphate level 0.61 mg/ woman dL) NAFLD Packed red blood [50] cells Vitamin D deficiency Severe asthenia FCM (initially FGF23 (427 RU/mL) 500 mg Q All other laboratory 2–3 months; most parameters (including recently 500 mg Q renal) normal 3 weeks) 32-year- Mixed connective tissue FCM 4 weeks prior Fatigue Hypophosphatemia (serum Severe hypophosphatemia old disorder to hospitalization Weakness phosphate 3.6 mg/dL at woman first FCM infusion) Rheumatoid arthritis Lightheadedness [51] Systemic lupus 1 week later serum erythematosus phosphate 1 mg/dL (repleted with 21 mmol IDA potassium phosphate) Remote history of After 3rd FCM infusion, pulmonary embolism serum phosphate \ 1 mg/ and CV accident dL 3543 3544 Table 1 continued Patient Relevant history Prior treatment Presentation Laboratory findings Diagnosis

65-year- Hereditary hemorrhagic Treated orally with Bone pain in both shoulders, Calcium, 9.2 mg/dL FGF23-mediated old man telangiectasia ferrous sulfate for pelvis, and all 4 limbs: worsened Phosphate 1.2 mg/L hypophosphatemic [52] (Rendu–Osler–Weber 15 years with movement osteomalacia ALP 356 U/L syndrome) Monthly FCM Required crutch and wheelchair 1,25(OH) D 21.8 ng/mL Chronic anemia due to treatment in prior 2 Bone scans showed multiple hot (optimal [ 30 ng/mL) intestinal blood loss 2 years spots and epistaxis 24-h urine calcium 46.8 mg, CT conﬁrmed multiple phosphate 0.44 g Sensorineural deafness insufﬁciency fractures FEPi 5.9% Type 2 diabetes cFGF23 [ 419 RU/mL Osteoporosis

1,25 (OH)2D 1,25-dihydrodroxyvitamin D, ALP alkaline phosphatase, cFGF23CT C-terminal FGF23 computed tomography, FCM ferric carboxymaltose, FEPi fractional excretion of phosphate, FGF23 fibroblast growth factor 23, HGB hemoglobin, HTN hypertension, IDA iron deficiency anemia, NAFLD non-alcoholic fatty liver disease, PINP procollagen type I N-terminal pro peptide, PTH pituitary thyroid hormone, TmP/GFR tubular maximum reabsorption of phosphate/glomerular filtration rate, ULN upper limit of normal d hr(01 38:3531–3549 (2021) Ther Adv Adv Ther (2021) 38:3531–3549 3545

Fig. 2 Patient diagnosed with symptomatic hypophos- Hyperintensities mark horizontal hypointensities extend- phatemia and osteomalacia with bilateral symmetric ing halfway across the femoral neck. b X-ray plain ﬁlm pseudofractures (looser zones) in the femur necks. a Mag- radiograph fails to show the fracture lines. Reprinted from netic resonance imaging showing marked hyperintensities Gastroenterology, 152(6), Benedikt Schaefer, Bernhard of both femoral necks on T1-weighted imaging using a Glodny, Heinz Zoller, Blood and Bone Loser, e5–e6, turbo inversion recovery magnitude sequence. Copyright (2017), with permission from Elsevier

Clinically significant hypophosphatemia IDA [43, 44]. Hypophosphatemia is not always following single or shorter courses of IV iron considered as a source of ongoing fatigue, formulations are less common but have been which instead is attributed to the underlying reported. One woman developed tiredness, dif- disease or to anemia despite evidence of reso- fuse muscle pain, and weakness after being lution of the IDA. In a retrospective review of treated twice with a single course of FCM patients with hypophosphatemia who received (500 mg) 3 weeks prior to her presenting with either FCM or iron sucrose, 55% reported her symptoms. Laboratory tests revealed severe improvement in fatigue symptoms. However, (0.23 mmol/L) hypophosphatemia [15]. 30% complained of fatigue worsening, and the Another patient presented with increasing fati- remainder reported no change in fatigue pre- gue and shortness of breath 3 weeks after fin- sumably because of severe hypophosphatemia ishing a course of FCM (dose not stated but since hemoglobin levels had been corrected assumed to be the indicated two doses of [24]. The diagnosis of iron-induced hypophos- 750 mg, since was reported from the USA). Her phatemia requires a high level of alertness and phosphate level was 1.2 mg/dL. Despite IV and suspicion and is based on recognizing its tem- oral treatment with phosphate, serum phos- poral association with a newly started IV iron phate remained critically low (0.72 mg/dL) and therapy [7]. she developed respiratory failure. Eventually symptoms resolved after IV administration of phosphate and calcitriol [21]. DISCUSSION Recognition of symptomatic hypophosphatemia is challenged by the fact that the most This review of renal phosphate wasting follow- common symptoms of acute hypophos- ing IV iron treatment has emphasized a number phatemia, fatigue and weakness, are also the of points. Larger, prospective trials have con- symptoms most commonly reported for IDA firmed that the incidence of severe hypophos- and for many of the chronic diseases that cause phatemia is very high following administration 3546 Adv Ther (2021) 38:3531–3549 of certain IV iron formulations; in those with exposure to FCM in patients without a history normal renal function the majority of patients of renal impairment.’’ The updated label also who are treated will experience a severe drop in notes that healthcare providers should ‘‘moni- serum phosphate. Comparative studies estab- tor serum phosphate levels in patients at risk for lish that almost exclusively this occurs follow- hypophosphatemia who require a repeat course ing FCM with negligible rates following iron of treatment’’. The Australian Department of dextran or ferumoxytol and a low but not neg- Health has also issued a safety alert to health- ligible incidence with iron sucrose or iron iso- care providers, noting that FCM (marketed as maltose (ferric derisomaltose). Although the Ferinject in Australia) is known to cause peak occurrence of hypophosphatemia is at hypophosphatemia that is usually mild and about 2–3 weeks post dose, more recent trials asymptomatic. They go on to state, however, establish that a large percentage of patients that it is also associated with a rare risk of severe continue to manifest severe hypophosphatemia symptomatic hypophosphatemia and echo ear- weeks and even months after the last dose of the lier recommendations in the literature that iron treatment. The larger, more recent trials healthcare providers ‘‘routinely evaluate patient have provided some understanding of patients risk factors before commencing Ferinject and who have heightened risk for the development follow up at-risk patients’’ [45]. Finally and most of severe hypophosphatemia. In general, and recently, the European Medicines Agency not surprisingly, this occurs much more com- modified the language required from ‘‘par- monly in patients with relatively normal renal enteral administered iron preparations can function. Future understanding of the duration cause hypophosphatemia which in most cases is of effect as well as the time course of the overall transient and without clinical symptoms’’ to phenomenon will require well-controlled trials ‘‘Symptomatic hypophosphatemia leading to that extend beyond the current 5–6 weeks. osteomalacia and fractures requiring clinical Most importantly, symptomatic cases con- intervention including surgery has been repor- tinue to accumulate. Although most usually ted in the post marketing setting. Patients occur after repetitive dosing, it is also clear that should seek medical advice if they experience symptoms can occur following even a single worsening fatigue with myalgias or bone pain. dose. Recognition of the latter is hampered by Serum phosphate should be monitored in the fact that the most common symptom is patients who receive multiple administrations fatigue, often inappropriately attributed to at higher doses or long-term treatment, and either the underlying causative condition for those with existing risk factors. In cases of per- the IDA or to persistence of anemia. sisting hypophosphatemia, treatment with fer- Contemporaneous to the preparation of this ric carboxymaltose should be re-evaluated.’’ review are actions by regulatory authorities that highlight the importance of this phenomenon and which, hopefully, will enhance the aware- CONCLUSIONS ness of it by clinicians. Presumably, these were driven by recognition of accumulating symp- This review emphasized that if clinicians are tomatic cases. The US prescribing information unaware of the occurrence and importance of for FCM (brand name Injectafer in the USA) had hypophosphatemia they are unlikely to appro- previously noted the incidence of hypophos- priately evaluate their patients, so the authors phatemia and described a single case. However, urge clinicians to retrain their thinking to in mid-February 2020, the US Food and Drug match the motto, ‘‘if you don’t look you will Administration updated the ‘‘warning and pre- never find’’ and to monitor serum phosphate cautions’’ section for FCM to acknowledge that levels, especially when using FCM. ‘‘symptomatic hypophosphatemia requiring clinical intervention has been reported in patients at risk of low serum phosphate. These cases have occurred mostly after repeated Adv Ther (2021) 38:3531–3549 3547

ACKNOWLEDGEMENTS NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction Funding. Funding for the journal’s Rapid in any medium or format, as long as you give Service and Open Access Fees Was provided by appropriate credit to the original author(s) and AMAG Pharmaceuticals Inc. The authors the source, provide a link to the Creative received no payment for their work. Commons licence, and indicate if changes were made. The images or other third party material Medical Writing and Editorial Assis- in this article are included in the article’s tance. Medical writing and editorial assistance Creative Commons licence, unless indicated was provided by Maria B. Vinall of The Curry otherwise in a credit line to the material. If Rockefeller Group, LLC, Tarrytown, NY, USA, material is not included in the article’s Creative and this assistance was funded by AMAG Phar- Commons licence and your intended use is not maceuticals Inc. permitted by statutory regulation or exceeds the permitted use, you will need to obtain permis- Authorship. All named authors meet the sion directly from the copyright holder. To view International Committee of Medical Journal a copy of this licence, visit http:// Editors (ICMJE) criteria for authorship for this creativecommons.org/licenses/by-nc/4.0/. article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published. REFERENCES Authorship Contributions. JAG, WES, and MW each participated in designing and con- 1. Okada M, Imamura K, Fuchigami T, et al. 2 cases of ceiving the review, contributed to each draft of nonspecific multiple ulcers of the small intestine the manuscript and reviewed the final draft of associated with osteomalacia caused by long-term intravenous administration of saccharated ferric the paper and approved its final submission. oxide. Nihon Naika Gakkai Zasshi. 1982;71(11): 1566–72. Disclosures. John A. Glaspy has served as a consultant to AMAG Pharmaceuticals Inc. and 2. Okada M, Imamura K, Iida M, Fuchigami T, Omae Luitpold Pharmaceuticals Inc. Myles Wolf has T. Hypophosphatemia induced by intravenous administration of saccharated iron oxide. Klin served as a consultant to AMAG Pharmaceuti- Wochenschr. 1983;61(2):99–102. cals Inc., Luitpold Pharmaceuticals Inc., and Pharmacosmos, Inc. William E. Strauss was a 3. Sato K, Nohtomi K, Demura H, et al. Saccharated full-time employee and held equity in AMAG ferric oxide (SFO)-induced osteomalacia: in vitro inhibition by SFO of bone formation and 1,25-di- Pharmaceuticals Inc. at the time of the initial hydroxy-vitamin D production in renal tubules. drafting of this manuscript. Bone. 1997;21(1):57–64.

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